The Diabetes Control and Complications Trial (DCCT, 1983-1993), randomized 1441 subjects with type 1 diabetes (T1DM) with no or minimal pre-existing complications to receive either intensive therapy aimed at near normal glycemia or conventional therapy aimed at maintenance of clinical well-being with no specific glucose targets. In 1993, after a mean follow-up of 6.5 yrs, the study showed an overwhelming benefit of intensive therapy that reduced the risks of retinopathy, nephropathy, and neuropathy by 35-76% compared to conventional therapy. The DCCT also showed that hyperglycemia was a primary determinant of complications, explored and described the features of Intensive therapy, including its effects on cardiovascular disease (CVD) risk factors, neurocognition and quality of life, and the projected health economic impact. DCCT intensive therapy was then adopted world-wide as standard-of-care for TIDM. The study, Epidemiology of Diabetes Interventions and its Complications (EDIC, 1994-present), is the observational follow-up study of the DCCT, using the same methods and following 95% of the surviving original cohort. Most outcomes are evaluated annually and CVD outcomes and deaths carefully documented and adjudicated. EDIC has notably discovered that the early beneficial effects of intensive treatment on complications have persisted for 10 years or more, despite the fact that HbA1c levels of the former DCCT intensive and conventional groups have been similar during EDIC. This phenomenon has been termed "metabolic memory." Remarkably, former Intensive therapy also reduced the risk of CVD events. The goals of the DCCT/EDIC for the next 5 years are to continue the assiduous follow-up to establish the life-long effects of intensive therapy, glycemia and other risk factors on diabetes complications, morbidity and mortality;to examine the durability and mechanisms of the metabolic memory phenomenon;describe the rates of progression to severe levels of microvascular complications (vision-threatening retinopathy, end stage renal disease, debilitating neuropathy) and CVD and mortality;perform epidemiologic analyses to investigate further the risk factors (including genetic factors) for diabetes complications across their entire spectrum of severity;determine the lifetime health economic Impact of DCCT intensive therapy based;and through additional funding applications, continue to expand and support investigators who will utilize the cohort, the phenotypic data set, and collected biologic and genetic samples to their greatest effect, expanding the knowledge regarding type 1 diabetes and its complications. PUBLIC HEALTH RELEVANCE: Subjects with diabetes, (1,500,000 insulin-dependent type 1 DM in the US) are at risk of microvascular and cardiovascular complications that are a major cause of morbidity, mortality and health care cost. The DCCT is continuing to demonstrate the long term benefits of near-normal glycemic control and to explore the mechanisms by which hyperglycemia leads to an increased risk of these adverse complications, potentially affording a future lifetime free of complications and a normal life expectancy for future generations.